ABSTRACT Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related deaths in the US. Due to intrinsic tumor resistance and underlying liver dysfunction, the availability of effective systemic chemotherapies for HCC remains very limited. Immunotherapy is a promising new treatment approach for HCC, but there are numerous barriers to immunotherapy in HCC, including an immunosuppressive microenvironment and the ?immunotolerance? of the liver. Thermal ablation can overcome these barriers by inducing hyperthermic cell stress, resulting in immunogenic tumoral cell death. However, conventional ablation modalities are limited by their lack of tumoral specificity, resulting in unavoidable thermal injury to adjacent normal tissues. This thermal injury can stimulate systemic tumor growth through the release of oncogenic inflammatory cytokines. Consequently, there is an unmet need for a tumor-specific ablation modality ideally suited to ?priming? the adaptive immune system against HCC. An ideal modality would maximize tumor hyperthermia, thus augmenting tumor-specific immune stimulation, and minimize thermal injury to adjacent tissue, thus preventing systemic tumor stimulation. By capitalizing on the exceptional localization of the clinically approved fluorescent drug indocyanine green (ICG) to HCC, we propose an ICG-based molecularly targeted photothermal ablation (MTPA) modality that will maximize tumor hyperthermic stress but minimize thermal injury to adjacent liver tissue. We hypothesize that MTPA will synergize with immune checkpoint inhibitor therapy and result in systemic tumoricidal immune activation with immunologic ?memory? but not the off-target oncogenic effects seen in conventional ablation. We will explore the adaptive immune response following MTPA in an orthotopic murine model of HCC in a background of liver cirrhosis. We will also test for hepatocyte injury and off-target oncogenic effects following MTPA compared to conventional ablation. This proposal builds upon the Principal Investigator's expertise in thermal ablation as well as optical molecular imaging. If successful, the proposed studies will establish a new clinically translatable, tumor-specific ablation modality for HCC. They will also greatly expand our knowledge of the immune/inflammatory ramifications of hyperthermia, knowledge that can be leveraged into tailoring locoregional therapies that result in maximal anti-tumor immune response. These advances can be combined synergistically with immune therapies to provide a potent systemic treatment for patients with advanced HCC.